The Journal of Pain
Volume 11, Issue 2 , Pages 119-130 , February 2010

Unilateral Focal Burn Injury Is Followed by Long-Lasting Bilateral Allodynia and Neuronal Hyperexcitability in Spinal Cord Dorsal Horn

  • Yu-Wen Chang

      Affiliations

    • Department of Neurology and Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, and Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut
  • ,
  • Andrew Tan

      Affiliations

    • Department of Neurology and Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, and Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut
  • ,
  • Carl Saab

      Affiliations

    • Department of Surgery, Rhode Island Hospital, Brown Alpert Medical School and Department of Neuroscience, Brown University, Providence, Rhode Island
  • ,
  • Stephen Waxman

      Affiliations

    • Department of Neurology and Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, and Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut
    • Corresponding Author InformationAddress reprint requests to Dr. Stephen G. Waxman, Chairman, Dept. of Neurology, Yale University School of Medicine, 333 Cedar Street, LCI-707, New Haven, CT 06510.

Received 6 May 2009 ,Revised 15 June 2009 ,Accepted 17 June 2009.

References 

  1. Arguis MJ, Perez J, Martinez G, Ubre M, Gomar C. Contralateral neuropathic pain following a surgical model of unilateral nerve injury in rats. Reg Anesth Pain Med. 2008;33:211–216
  2. Baumann TK, Simone DA, Shain CN, LaMotte RH. Neurogenic hyperalgesia: The search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia. J Neurophysiol. 1991;66:212–227
  3. Brenowitz GL. Timecourse for receptive field plasticity following spinal cord hemisection. Brain Res. 1983;279:250–253
  4. Chacur M, Milligan ED, Gazda LS, Armstrong C, Wang H, Tracey KJ, et al. A new model of sciatic inflammatory neuritis (SIN): Induction of unilateral and bilateral mechanical allodynia following acute unilateral peri-sciatic immune activation in rats. Pain. 2001;94:231–244
  5. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53:55–63
  6. Chapman V, Suzuki R, Dickenson AH. Electrophysiological characterization of spinal neuronal response properties in anaesthetized rats after ligation of spinal nerves L5-L6. J Physiol. 1998;507(Pt 3):881–894
  7. Christensen MD, Hulsebosch CE. Chronic central pain after spinal cord injury. J Neurotrauma. 1997;14:517–537
  8. Christensen MD, Hulsebosch CE. Spinal cord injury and anti-NGF treatment results in changes in CGRP density and distribution in the dorsal horn in the rat. Exp Neurol. 1997;147:463–475
  9. Crown ED, Gwak YS, Ye Z, Johnson KM, Hulsebosch CE. Activation of p38 MAP kinase is involved in central neuropathic pain following spinal cord injury. Exp Neurol. 2008;213:257–267
  10. Dauber A, Osgood PF, Breslau AJ, Vernon HL, Carr DB. Chronic persistent pain after severe burns: a survey of 358 burn survivors. Pain Med. 2002;3:6–17
  11. Dirig DM, Salami A, Rathbun ML, Ozaki GT, Yaksh TL. Characterization of variables defining hindpaw withdrawal latency evoked by radiant thermal stimuli. J Neurosci Methods. 1997;76:183–191
  12. Dixon WJ. Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol. 1980;20:441–462
  13. Hains BC, Klein JP, Saab CY, Craner MJ, Black JA, Waxman SG. Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. J Neurosci. 2003;23:8881–8892
  14. Hains BC, Saab CY, Klein JP, Craner MJ, Waxman SG. Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury. J Neurosci. 2004;24:4832–4839
  15. Hains BC, Waxman SG. Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J Neurosci. 2006;26:4308–4317
  16. Hains BC, Willis WD, Hulsebosch CE. Temporal plasticity of dorsal horn somatosensory neurons after acute and chronic spinal cord hemisection in rat. Brain Res. 2003;970:238–241
  17. Hua XY, Svensson CI, Matsui T, Fitzsimmons B, Yaksh TL, Webb M. Intrathecal minocycline attenuates peripheral inflammation-induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Eur J Neurosci. 2005;22:2431–2440
  18. Hucho T, Levine JD. Signaling pathways in sensitization: Toward a nociceptor cell biology. Neuron. 2007;55:365–376
  19. Hulsebosch CE, Hains BC, Crown ED, Carlton SM. Mechanisms of chronic central neuropathic pain after spinal cord injury. Brain Res Rev. 2008 Dec 25;[Epub ahead of print]
  20. Hunt SP, Mantyh PW. The molecular dynamics of pain control. Nat Rev Neurosci. 2001;2:83–91
  21. Ji RR, Gereau RWt, Malcangio M, Strichartz GR. MAP kinase and pain. Brain Res Rev. 2008;
  22. Ji RR, Suter MR. p38 MAPK, microglial signaling, and neuropathic pain. Mol Pain. 2007;3:33
  23. Jin SX, Zhuang ZY, Woolf CJ, Ji RR. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci. 2003;23:4017–4022
  24. Kim SY, Bae JC, Kim JY, Lee HL, Lee KM, Kim DS, et al. Activation of p38 MAP kinase in the rat dorsal root ganglia and spinal cord following peripheral inflammation and nerve injury. Neuroreport. 2002;13:2483–2486
  25. Klein MB, Lezotte DL, Fauerbach JA, Herndon DN, Kowalske KJ, Carrougher GJ, et al. The National Institute on Disability and Rehabilitation Research burn model system database: A tool for the multicenter study of the outcome of burn injury. J Burn Care Res. 2007;28:84–96
  26. Koltzenburg M, Wall PD, McMahon SB. Does the right side know what the left is doing?. Trends Neurosci. 1999;22:122–127
  27. LaMotte RH, Lundberg LE, Torebjork HE. Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin. J Physiol. 1992;448:749–764
  28. Ledeboer A, Sloane EM, Milligan ED, Frank MG, Mahony JH, Maier SF, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain. 2005;115:71–83
  29. Lee SE, Kim JH. Involvement of substance P and calcitonin gene-related peptide in development and maintenance of neuropathic pain from spinal nerve injury model of rat. Neurosci Res. 2007;58:245–249
  30. Lin T, Li K, Zhang FY, Zhang ZK, Light AR, Fu KY. Dissociation of spinal microglia morphological activation and peripheral inflammation in inflammatory pain models. J Neuroimmunol. 2007;192:40–48
  31. Ma W, Quirion R. Partial sciatic nerve ligation induces increase in the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in astrocytes in the lumbar spinal dorsal horn and the gracile nucleus. Pain. 2002;99:175–184
  32. Malan TP, Ossipov MH, Gardell LR, Ibrahim M, Bian D, Lai J, et al. Extraterritorial neuropathic pain correlates with multisegmental elevation of spinal dynorphin in nerve-injured rats. Pain. 2000;86:185–194
  33. Malcangio M, Ramer MS, Jones MG, McMahon SB. Abnormal substance P release from the spinal cord following injury to primary sensory neurons. Eur J Neurosci. 2000;12:397–399
  34. Malenfant A, Forget R, Amsel R, Papillon J, Frigon JY, Choiniere M. Tactile thermal and pain sensibility in burned patients with and without chronic pain and paresthesia problems. Pain. 1998;77:241–251
  35. Mantyh PW, Rogers SD, Honore P, Allen BJ, Ghilardi JR, Li J, et al. Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor. Science. 1997;278:275–279
  36. Milligan ED, Twining C, Chacur M, Biedenkapp J, O'Connor K, Poole S, et al. Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci. 2003;23:1026–1040
  37. Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009;10:23–36
  38. Montgomery RK. Pain management in burn injury. Crit Care Nurs Clin North Am. 2004;16:39–49
  39. Neumann S, Doubell TP, Leslie T, Woolf CJ. Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons. Nature. 1996;384:360–364
  40. Nikodemova M, Duncan ID, Watters JJ. Minocycline exerts inhibitory effects on multiple mitogen-activated protein kinases and IkappaBalpha degradation in a stimulus-specific manner in microglia. J Neurochem. 2006;96:314–323
  41. Nozaki-Taguchi N, Yaksh TL. A novel model of primary and secondary hyperalgesia after mild thermal injury in the rat. Neurosci Lett. 1998;254:25–28
  42. Paxinos G, Watson C. The Rat Brain: In. Stereotaxia Coordinates. Burlington, MA: Academic Press; 1998;
  43. Saab CY, Hains BC. Remote neuroimmune signaling: A long-range mechanism of nociceptive network plasticity. Trends Neurosci. 2009;32:110–117
  44. Scholz J, Woolf CJ. The neuropathic pain triad: Neurons, immune cells and glia. Nat Neurosci. 2007;10:1361–1368
  45. Schreiber KL, Beitz AJ, Wilcox GL. Activation of spinal microglia in a murine model of peripheral inflammation-induced, long-lasting contralateral allodynia. Neurosci Lett. 2008;440:63–67
  46. Simone DA, Sorkin LS, Oh U, Chung JM, Owens C, LaMotte RH, et al. Neurogenic hyperalgesia: Central neural correlates in responses of spinothalamic tract neurons. J Neurophysiol. 1991;66:228–246
  47. Sinnott CJ, Garfield JM, Strichartz GR. Differential efficacy of intravenous lidocaine in alleviating ipsilateral versus contralateral neuropathic pain in the rat. Pain. 1999;80:521–531
  48. Sorkin L, Svensson CI, Jones-Cordero TL, Hefferan MP, Campana WM. Spinal p38 mitogen-activated protein kinase mediates allodynia induced by first-degree burn in the rat. J Neurosci Res. 2009;87:948–955
  49. Summer GJ, Dina OA, Levine JD. Enhanced inflammatory hyperalgesia after recovery from burn injury. Burns 33. 2007;1021–1026
  50. Summer GJ, Puntillo KA, Miaskowski C, Dina OA, Green PG, Levine JD. TrkA and PKC-epsilon in thermal burn-induced mechanical hyperalgesia in the rat. J Pain. 2006;7:884–891
  51. Summer GJ, Puntillo KA, Miaskowski C, Green PG, Levine JD. Burn injury pain: The continuing challenge. J Pain. 2007;8:533–548
  52. Summer GJ, Romero-Sandoval EA, Bogen O, Dina OA, Khasar SG, Levine JD. Proinflammatory cytokines mediating burn-injury pain. Pain. 2008;135:98–107
  53. Sung B, Lim G, Mao J. Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J Neurosci. 2003;23:2899–2910
  54. Suzuki R, Kontinen VK, Matthews E, Williams E, Dickenson AH. Enlargement of the receptive field size to low intensity mechanical stimulation in the rat spinal nerve ligation model of neuropathy. Exp Neurol. 2000;163:408–413
  55. Tal M, Bennett GJ. Extra-territorial pain in rats with a peripheral mononeuropathy: Mechano-hyperalgesia and mechano-allodynia in the territory of an uninjured nerve. Pain. 1994;57:375–382
  56. Torebjork HE, Lundberg LE, LaMotte RH. Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol. 1992;448:765–780
  57. Tsuda M, Inoue K, Salter MW. Neuropathic pain and spinal microglia: A big problem from molecules in “small” glia. Trends Neurosci. 2005;28:101–107
  58. Tsuda M, Mizokoshi A, Shigemoto-Mogami Y, Koizumi S, Inoue K. Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia. 2004;45:89–95
  59. Ueda M, Hirose M, Takei N, Ibuki T, Naruse Y, Ibata Y, et al. Foot hyperalgesia after thoracic burn injury - Histochemical, behavioral and pharmacological studies. Acta Histochem Cytochem. 2001;34:441–450
  60. Wang S, Lim G, Yang L, Zeng Q, Sung B. Jeevendra Martyn JA, Mao J: A rat model of unilateral hindpaw burn injury: slowly developing rightwards shift of the morphine dose-response curve. Pain. 2005;116:87–95
  61. Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature. 1983;306:686–688
  62. Zhang F, Vadakkan KI, Kim SS, Wu LJ, Shang Y, Zhuo M. Selective activation of microglia in spinal cord but not higher cortical regions following nerve injury in adult mouse. Mol Pain. 2008;4:15

 Supported by grants from the Medical Research Service and Rehabilitation Research Service, Department of Veterans Affairs.

PII: S1526-5900(09)00607-5

doi: 10.1016/j.jpain.2009.06.009

The Journal of Pain
Volume 11, Issue 2 , Pages 119-130 , February 2010